PROJECT SUMMARY/ABSTRACT In the US, colorectal cancer is the third most commonly diagnosed cancer in men and women. An increasing number of studies are suggesting that bacteria play a role in colorectal cancer, including oral bacteria that have the potential to act as pathobionts. In addition, recent studies have shown that periodontitis is associated with an elevated risk of colorectal cancer. In a recent Science article, Bullman et al. identified a high relative abundance of Fusobacterium in many colorectal primary tumors as well as in metastatic tumors, and they also reported the presence of many other bacteria in colorectal tumors, including bacteria previously associated with periodontitis (e.g,. Treponema denticola) and colorectal cancer (e.g., Bacteroides fragilis). While Fusobacterium nucleatum has been studied extensively in relation to colorectal cancer, Porphyromonas gingivalis, a keystone pathogen for periodontal disease, has been less well-studied, although two studies suggest it may be associated with colorectal cancer. These studies provide strong rationale to more thoroughly investigate the role of oral pathobionts in colorectal carcinogenesis. In this R21, in Aim 1 we propose to evaluate if serum antibodies to 8 periodontal pathobionts are associated with colon cancer risk and will assess latency up to 25 years in a prospective study of 200 cases and 200 matched controls nested in a cohort with long follow-up. In Aim 2, we will optimize an existing method for measuring antibodies to periodontal microbiota in plasma, and then determine the correlation between antibody concentrations in serum and plasma from the same participants over a 15-year time period. The advantage of using circulating concentration of antibodies as a measure of exposure to periodontal disease bacteria is that it reflects the extent to which the bacteria have invaded the host beyond the oral cavity and elicited an immune response. The proposed study will be the first to examine the association between antibodies to periodontal disease microbiota and colon cancer risk using prediagnostic blood samples, and by informing on the temporal relationship will provide critical data to further evaluate the causal role of periodontal microbiota on cancer development in humans.